This proposal consisting of five projects focuses on the analysis of the mechanisms leading to malignant transformation of hematopoietic cells with emphasis on retroviruses and oncogenes. The theme is to define the genes that contribute to malignant transformation resulting in leukemias and lymphomas and the mechanisms by which oncogenes and viruses interfere with normal differentiation pathways of various hematopoietic lineages. We will focus on five oncogenes, myb, fos, jun, abl and ras to increase our understanding of their mode of action at the molecular and cellular level. We will explore the possibility of using the MoMuLV as a tool to identify potential oncogene candidates, by insertional mutagenesis in vitro, on a growth-factor dependent cell line. We will study the molecular mechanism of action of newly identified transforming gene of a recently described virus (HHV6) to understand its mechanism of action and role in human hematopoietic malignancies. Finally, we will look at the role played by HIV1 and DNA viruses to define the molecular basis of hyperplasia in AIDS patients and to determine the criteria for identifying progressive lymphomas at an early stage of development.